Efficacy and safety of upadacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to biological treatments: results through 5 years from the SELECT-BEYOND study

Abstract

Objective: To evaluate the efficacy and safety of upadacitinib over 5 years among patients with rheumatoid arthritis (RA) in a long-term extension (LTE) of the SELECT-BEYOND phase 3 trial.

Methods: Patients refractory to ≥1 biological disease-modifying antirheumatic drug (DMARD) received upadacitinib 15 mg or 30 mg once daily or placebo, in combination with background conventional synthetic DMARD(s). At week 12, patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg. All patients who completed the week 24 visit could enter the LTE for up to 5 years. Efficacy was analysed as observed and by non-responder imputation through week 260. Treatment-emergent adverse events per 100 patient-years were summarised over 5 years.

Results: Of the 498 patients randomised, 418 (84%) completed week 24 and entered the LTE. Of those who remained in the trial (n=80, upadacitinib 15 mg; n=81, upadacitinib 30 mg), 36%/36% and 81%/77% randomised to upadacitinib 15/30 mg were in Clinical Disease Activity Index (CDAI) remission or low disease activity at week 260, respectively (as observed). Approximately 47% of all patients who began in high disease activity demonstrated a CDAI improvement >12 at week 260 with upadacitinib 15/30 mg. Functional and pain-related outcomes also showed comparable improvements with both doses. Numerically higher rates of anaemia, herpes zoster and creatine phosphokinase elevation were observed with upadacitinib 30 mg vs 15 mg. No new safety issues were identified.

Conclusions: Upadacitinib 15/30 mg continued to be effective in treating clinical and functional outcomes in patients with RA. The safety profile observed over 5 years was consistent with earlier study-specific and integrated assessments of upadacitinib treatment.

Keywords: Antirheumatic Agents; Rheumatoid Arthritis; Therapeutics.

Figure 1. Disposition of patients through 5 years in SELECT-BEYOND. ^aThe numbers of patients in each treatment group are shown, with the primary reason for discontinuation listed during the LTE through week 260. ^bA total of 499 patients were randomly assigned (n=165, UPA 15 mg; n=165, UPA 30 mg; n=85, PBO then UPA 15 mg; n=84, PBO then UPA 30 mg), but one patient withdrew from the UPA 15 mg group before the start of study treatment due to accidental randomisation. ^cPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. AE, adverse event; D/C, discontinued; f/u, follow-up; inf, infection; l/c, logistical constraints; LoE, lack of efficacy; LTE, long-term extension; PBO, placebo; QD, once daily; UPA, upadacitinib; W, week.

Figure 2. Proportions of patients achieving CDAI or DAS28(CRP) disease activity states through 5 years (AO). Data are from patients who were initially randomised to UPA 15 mg or 30 mg and those who switched from PBO to either dose of UPA at week 12. The total number of patients (n) in each treatment group are shown at weeks 4, 24, 48, 96, 156, 204 and 260. Cut points for CDAI were ≤2.8 for remission and ≤10 for LDA. ^aPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. AO, as observed; CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C reactive protein; LDA, low disease activity; PBO, placebo; QD, once daily; UPA, upadacitinib.

Figure 3. Proportions of patients achieving CDAI or DAS28(CRP) disease activity states through 5 years (NRI). Data are from patients who were initially randomised to UPA 15 mg or 30 mg and those who switched from PBO to either dose of UPA at week 12. Cut points for CDAI were ≤2.8 for remission and ≤10 for LDA. ^aPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C reactive protein; LDA, low disease activity; NRI, non-responder imputation; PBO, placebo; QD, once daily; UPA, upadacitinib.

Figure 4. Proportions of patients starting in high disease activity with CDAI improvement >12 at week 260 (AO). Minimal clinically important differences in CDAI were previously defined as >12 for patients in high disease activity (Curtis et al, 2015). The number of patients starting in high desease activity who achieved a CDAI improvement >12 (n) and the total number of patients in each treatment group (N) at week 260 are shown. ^aHigh disease activity was defined as CDAI >22. ^bPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. AO, as observed; CDAI, Clinical Disease Activity Index; PBO, placebo; QD, once daily; UPA, upadacitinib.

Figure 5. Proportions of patients achieving ACR20/50/70 responses through 5 years (AO). Data are from patients who were initially randomised to UPA 15 mg or 30 mg and those who switched from PBO to either dose of UPA at week 12. A total number of patients (n) in each treatment group are shown at weeks 4, 24, 48, 96, 156, 204 and 260. ^aPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. ACR20/50/70, ≥20%/50%/70% improvement in American College of Rheumatology response criteria; AO, as observed; PBO, placebo; QD, once daily; UPA, upadacitinib.

Figure 6. Proportions of patients achieving ACR20/50/70 responses through 5 years (NRI). Data are from patients who were initially randomised to UPA 15 mg or 30 mg and those who switched from PBO to either dose of UPA at week 12. ^aPatients in the UPA 30 mg treatment group were switched to receiving UPA 15 mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 180 visit. ACR20/50/70, ≥20%/50%/70% improvement in American College of Rheumatology response criteria; NRI, non-responder imputation; PBO, placebo; QD, once daily; UPA, upadacitinib.